Laromustine (cloretazine)

Expert Opinion on Pharmacotherapy

Volumn 11, Issue 4, 2010, Pages 657-667

  Vey, Norbert ^a   Giles, Frank ^b  

^a INSTITUT PAOLI CALMETTES   (France)

^b CTRC Institute for Drug Development   (United States)

Author keywords

Acute myeloid leukemia; Alkylating agents; Elderly; Induction chemotherapy; Myelodysplastic syndrome

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; BORTEZOMIB; CALICHEAMICIN; CLOFARABINE; CLORETAZINE; CYTARABINE; EVEROLIMUS; FLUDARABINE; GEMTUZUMAB OZOGAMICIN; LESTAURTINIB; MIDOSTAURIN; PANOBINOSTAT; RAPAMYCIN; SUNITINIB; TANDUTINIB; TEMOZOLOMIDE; TIPIFARNIB; VALPROIC ACID; VALSPODAR; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; ASTHENIA; CANCER RELAPSE; CLINICAL TRIAL; COLITIS; DIARRHEA; DIZZINESS; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; FLUSHING; HEADACHE; HUMAN; HYPOTENSION; LEG CRAMP; MUCOSA INFLAMMATION; MYELODYSPLASTIC SYNDROME; NAUSEA; NEUTROPENIA; REVIEW; SIDE EFFECT; SUPRAVENTRICULAR TACHYCARDIA; THROMBOCYTOPENIA;

AGED; ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE II AS TOPIC; DRUG EVALUATION, PRECLINICAL; HUMANS; HYDRAZINES; LEUKEMIA, MYELOID, ACUTE; REMISSION INDUCTION; SULFONAMIDES; TREATMENT OUTCOME;

EID: 77249119390     PISSN: 14656566     EISSN: None     Source Type: Journal    
DOI: 10.1517/14656561003621232     Document Type: Review

References (84)

1. Taylor PR, Reid MM, Stark AN, et al. De novo acute myeloid leukaemia in patients over 55-years-old: a population-based study of incidence, treatment and outcome. Northern Region Haematology Group. Leukemia 1995;9:231-7
2. Burnett AK, Eden OB. The treatment of acute leukaemia. Lancet 1997;349:270-5
3. Keating MJ, Smith TL, Kantarjian H, et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988;2:403-12
4. Dastugue N, Payen C, Lafage-Pochitaloff M, et al. Prognostic significance of karyotype in de novo adult acute myeloid leukemia. The BGMT group. Leukemia 1995;9:1491-8
5. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998;92:2322-33
6. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adults acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000;96:4075-83
7. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36
8. Baldus CD, Mrozek K, Marcucci G, Bloomfield CD. Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review. Br J Haematol 2007;137:387-400
9. Schlenk RF, Dohner K. Impact of new prognostic markers in treatment decisions in acute myeloid leukemia. Curr Opin Hematol 2009;16:98-104
10. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909-18 • This study identified NPM1 mutated/FLT3 wild-type AMLs as a group of favorable prognosis among AML with normal cytogentics.
11. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642-9
12. Group TAC. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br J Haematol 1998;103:100-9
13. Estey E, Dohner H. Acute myeloid leukaemia. Lancet 2006;368:1894-907 •• Excellent review on AML.
14. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331:896-903 • The trial that demonstrated the pivotal role of HDAC in the postremission treatment of AML in younger patients.
15. Burnett AK. Transplantation in first remission of acute myeloid leukemia. N Engl J Med 1998;339:1698-700
16. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998;339:1649-56
17. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 1997;90:2978-86
18. Reiffers J, Stoppa AM, Attal M, et al. Autologous stem cell transplantation versus chemotherapy for adult patients with acute myeloid leukemia in first remission: the BGMT Group experience. Nouv Rev Fr Hematol 1993;35:17-9
19. Vey N, Coso D, Bardou VJ, et al. The benefit of induction chemotherapy in patients age > or = 75 years. Cancer 2004;101:325-31
20. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995;332:217-23
21. Blaise DP, Michel Boiron J, Faucher C, et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 2005;104(9):1931-8
22. Keating M, Kantarjian H, Smith T, et al. Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 1989;7:1071-80
23. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005;23:1969-78 • One of the largest studies on relapsed AML and prognostic factors.
24. Vey N, Keating M, Giles F, et al. Effect of complete remission on survival in patients with acute myelogenous leukemia receiving first salvage therapy. Blood 1999;93:3149-50
25. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 2000;14:476-9
26. Pinto A, Zagonel V, Ferrara F. Acute myeloid leukemia in the elderly: biology and therapeutic strategies. Crit Rev Oncol Hematol 2001;39:275-87
27. Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood 2007;109:5129-35
28. Pigneux A, Perreau V, Jourdan E, et al. Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results. Haematologica 2007;92:1327-34
29. Rowe JM, Neuberg D, Friedenberg W, et al. A Phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004;103:479-85
30. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109:1114-24
31. Larson RA, Boogaerts M, Estey E, et al. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia 2002;16:1627-36
32. Burnett A, Kell W, Goldstone A, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 trial. ASH Annual Meeting Abstracts. Blood 2006;108:13
33. Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004:98-117
34. Faderl S, Gandhi V, Keating MJ, et al. The role of clofarabine in hematologic and solid malignancies - development of a next-generation nucleoside analog. Cancer 2005;103:1985-95
35. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 2003;102:2379-86
36. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004;103:784-9
37. Faderl S, Gandhi V, O'Brien S, et al. Results of a Phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 2005;105:940-7
38. Erba H, Kantarjian H, Claxton D, et al. Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. J Clin Oncol 2008;26(20 Suppl):abstract 7025
39. O'Brien S, Vey N, Rizzieri D, et al. A phase I study with CP-4055 in patients with hematologic malignancies. J Clin Oncol 2008;26(20 Suppl):abstract 2532
40. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a Phase 1 clinical-laboratory correlative trial. Blood 2001;97:3361-9
41. Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized Phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009;114:1166-73
42. Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 2009;33:348-50
43. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004;103:3669-76
44. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:54-60
45. Recher C, Beyne-Rauzy O, Demur C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005;105:2527-34
46. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32
47. Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 2009;27:3842-8
48. Garcia-Manero G. Demethylating agents in myeloid malignancies. Curr Opin Oncol 2008;20:705-10
49. Dombret H, Raffoux E, Gardin C. Acute myeloid leukemia in the elderly. Semin Oncol 2008;35:430-8 • Excellent review addressing treatment difficulties and new options for elderly patients with AML.
50. Ades L, Boehrer S, Prebet T, et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a Phase 2 study. Blood 2009;113:3947-52
51. Costello RT, Fauriat C, Rey J, et al. Immunobiology of haematological malignant disorders: the basis for novel immunotherapy protocols. Lancet Oncol 2004;5:47-55
52. Brune M, Castaigne S, Catalano J, et al. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized Phase 3 trial. Blood 2006;108:88-96
53. Oka Y, Tsuboi A, Fujiki F, et al. WT1 Peptide vaccine as a paradigm for "cancer antigen-derived peptide"-based immunotherapy for malignancies: successful induction of anti-cancer effect by vaccination with a single kind of WT1 peptide. Anticancer Agents Med Chem 2009;9(7):787-97
54. Romagne F, Andre P, Spee P, et al. Pre-clinical characterization of 1-7F9, a novel human anti-KIR therapeutic antibody that augments NK-mediated killing of tumor cells. Blood 2009;114(13):2667-77
55. Vey N, Bourhis J, Dombret H, et al. A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1-7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML). J Clin Oncol 2009;27(15s):abstract 3015
56. Penketh PG, Shyam K, Sartorelli AC. Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl) hydrazines and chloroethylnitrosoureas. Biochem Pharmacol 2000;59:283-91
57. Briscoe WT, Duarte SP. Preferential alkylation by 1,3-bis(2-chloroethyl)- 1-nitrosourea (BCNU) of guanines with guanines as neighboring bases in DNA. Biochem Pharmacol 1988;37:1061-6
58. Baumann RP, Seow HA, Shyam K, et al. The antineoplastic efficacy of the prodrug cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation. Oncol Res 2005;15:313-25
59. Ishiguro K, Seow HA, Penketh PG, et al. Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine. Mol Cancer Ther 2006;5:969-76
60. Penketh PG, Baumann RP, Ishiguro K, et al. Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species. Leuk Res 2008;32:1546-53
61. Frederick AM, Davis ML, Rice KP. Inhibition of human DNA polymerase beta activity by the anticancer prodrug cloretazine. Biochem Biophys Res Commun 2009;378:419-23
62. Finch RA, Shyam K, Penketh PG, Sartorelli AC. 1,2-Bis(methylsulfonyl)-1- (2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broad-spectrum antineoplastic activity. Cancer Res 2001;61:3033-8
63. Pratviel G, Shyam K, Sartorelli AC. Cytotoxic and DNA-damaging effects of 1,2-bis(sulfonyl)hydrazines on human cells of the Mer+ and Mer- phenotype. Cancer Biochem Biophys 1989;10:365-75
64. D'Atri S, Piccioni D, Castellano A, et al. Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients. Ann Oncol 1995;6:389-93
65. Gerson SL, Trey JE. Modulation of nitrosourea resistance in myeloid leukemias. Blood 1988;71:1487-94
66. Gerson S, O'Brien S, Donze J, et al. Analysis of pre-treatment O6-alkylguanine transferase (AGT) levels in patients (pts) with hematologic malignancies receiving VNP40101M (101M). J Clin Oncol 2005;23:abstract 6542
67. Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 2002;20:2388-99
68. Seiter K, Liu D, Loughran T, et al. Phase I study of temozolomide in relapsed/refractory acute leukemia. J Clin Oncol 2002;20:3249-53
69. Murren J, Modiano M, Kummar S, et al. A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer. Invest New Drugs 2005;23:123-35 • Initial Phase I trial of laromustine (cloretazine) in solid tumors which showed thrombocytopenia to be dose limiting.
70. Giles F, Thomas D, Garcia-Manero G, et al. A Phase I and pharmacokinetic study of VNP40101M, a novel sulfonylhydrazine alkylating agent, in patients with refractory leukemia. Clin Cancer Res 2004;10:2908-17 •• The Phase I study of laromustine (cloretazine) in hematologic malignancies which established the recommended dose.
71. Giles F, Verstovsek S, Faderl S, et al. A Phase II study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients with very high risk relapsed acute myeloid leukemia. Leuk Res 2006;30:1591-5 • This study showed limited clinical activity of laromustine as a single agent in patients with advanced AML.
72. Giles F, Rizzieri D, Karp J, et al. Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 2007;25:25-31 •• A large, multicenter, Phase II trial of laromustine in elderly patients with AML which showed promising response rate and confirmed the good tolerance in this patients.
73. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-19
74. Schiller G, O'Brien S, Pigneux A, et al. Single agent laromustine (VNP40101M), a novel alkylating agent, has significant activity in older patients with previously untreated poor-risk acute myeloid leukemia. J Clin Oncol 2009 [Epub ahead of print] •• This study confirmed the therapeutic potential of laromustine single agent as an alternative to intensive chemotherapy for elderly AML patients with comorbidities who are generally not offered induction chemotherapy.
75. Giles F, Verstovsek S, Thomas D, et al. Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia. Clin Cancer Res 2005;11:7817-24 • This study evaluated the tolerance of a combination of laromustine and HDAC in patients with advanced AML.
76. Giles F, Vey N, Deangelo D, et al. Phase III randomized, placebo-controlled, double-blind study of high dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood 2009;114(19):4027-33 •• This large comparative trial showed that laromustine/HDAC was superior to placebo/HDAC in terms of complete remission. However, because of superior mortality rate, survival was not improved. This raises questions regarding laromustine dose and patient selection for future combination trials.
77. Frei E III, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980;69:585-94
78. Maraninchi D, Pico JL, Hartmann O, et al. High-dose melphalan with or without marrow transplantation: a study of dose-effect in patients with refractory and/or relapsed acute leukemias. Cancer Treat Rep 1986;70:445-8
79. Breems DA, Lowenberg B. Autologous stem cell transplantation in the treatment of adults with acute myeloid leukaemia. Br J Haematol 2005;130:825-33
80. Mascret B, Maraninchi D, Gastaut JA, et al. Repeated high-dose-melphalan with autologous bone marrow transplantation in acute non lymphocytic leukemia. Rev Fr Transfus Immunohematol 1985;28:477-88
81. Bug G, Atta J, Klein SA, et al. High-dose melphalan is an effective salvage therapy in acute myeloid leukaemia patients with refractory relapse and relapse after autologous stem cell transplantation. Ann Hematol 2005;84:748-54
82. Etienne A, Esterni B, Charbonnier A, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer 2007;109:1376-83
83. Malfuson JV, Etienne A, Turlure P, et al. Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia. Haematologica 2008;93:1806-13
84. Morris KL, Adams JA, Liu Yin JA. Effect of cloretazine (VNP40101M) on acute myeloid leukaemia blast cells in vitro as a single agent and combined with cytarabine and daunorubicin. Leuk Res 2009;33:1096-9